Rajiv Gandhi University of Health Sciences, Karnataka s32

“SYNTHESIS, CHARACTERISATION AND CYTOTOXIC EVALUATION OF RESVERATROL/COLCHICINE TYPE OF COMPOUNDS”

SYNOPSIS FOR REGISTRATION OF M.PHARM DISSERTATION

Submitted to

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA

G.RAVINDRA REDDY I .M.PHARM

Department Of Pharmaceutical Chemistry DAYANANDA SAGAR COLLEGE OF PHARMACY 2010 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA BANGALORE ANNEXURE - II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. Name of the Candidate G.RAVINDRA REDDY and Address S/O. G.CH.RAMI REDDY D.NO:3-273-B, Professors colony, Yerramukka palli, Kadapa-516004

2. Name of the Institution Dayananda Sagar College of Pharmacy, Kumaraswamy layout, Bangalore – 560 078.

3. Course of Study and M. Pharm in Pharmaceutical Chemistry. Subject

4. Date of Admission 21- JUNE-2010

5. Title of The topic :

“SYNTHESIS, CHARACTERISATION AND CYTOTOXIC EVALUATION OF RESVERATROL/COLCHICINE TYPE OF COMPOUNDS” R =various substitutions

6.0 Brief resume of the intended work:

6.1 – Need for the study:

The synthesis, characterisation and cytotoxic evaluation of RESVERATROL/COLCHICINE

type of compounds (substituted resveratrol derivatives) have long been the focus of

research interests in the field of medicine. A number of derivatives of

RESVERATROL/COLCHICINE type of compounds have been reported to possess

several biological activities including anticancer1-5, neuroprotective6, cardioprotective7,

anti inflammatory8, 9, and antiviral10activity.

Resveratrol is naturally occurring phyloalexin found in several plants but mainly in the

skin grapes. Resveratrol is believed to be synthesised by Plants to protect themselves

against fungal pathogen, oxidative stress and u.v radiation. It has become increasingly

clear that resveratrol possesses a number of health benefits to human and is important in

treatment of various disease/disorders involving cardiovascular system and in various

neoplasms.Resveratrol derivatives have been identified as an effective candidate for

cancer chemotherapy due to its ability to block each step in the carcinogenesis process

namely tumor initiation, promotion and progression. It has also been shown to suppress

angiogenesis and metastasis. Extensive data in human cell cultures indicate that

resveratrol derivatives can modulate multiple pathways involved in cell growth, apoptosis

and inflammation. Based on the available literature, our objective is to synthesise various

Resveratrol/colchicines type of compounds, characterizing all the synthesised compounds

by various spectral analysis and to screen them for cytotoxic activity. SCHEME: Trisubstituted aryl aldehyde is converted to highly substituted stilbene derivatives (resveratrol/colchicines type compounds) via chalcone formation and various chemical reactions. The synthesis of the titled compounds involves essentially 4 steps.

R7 O R R3 4steps 3 H R6

R5 R R2 2

R1 R1 R4

6.2 – Review of the literature:

1. Eun-jin lee, Hye-young et al1, have reported the G2/M cell cycle arrest and induction of apoptosis by a stilbenoid, 3,4,5-trimethoxy-41-bromo-cis-stilbene, in human lung cancer cells.

2. Brian w.moran et al2, have reported the synthesis, structural characterization and biological evaluation of fluorinated analogues of resveratrol.

3. Marex murias et al3, have reported the antioxidant prooxidant and cytotoxic activity of hydroxylated resveratrol analogues while studying their structural-activity relationship.

4 4. P.Nigro et al , have reported the Antiproliferative and proapoptotic activity of novel phenolic derivatives of resveratrol. 5 5. Mahammad Athar et al , have reported the resveratrol: A review of preclinal studies for human cancer prevention.

6. Stephane Bastianetto et al6, have reported the neuroprotective abilities of resveratrol and other red wine constituents against nitric oxide-related toxicity in cultured hippocampal neurons.

7 7. Philipp.saiko et al , have reported about the resveratrol and its analogs: defense against cancer, coronary disease and neurodegenerative maladies or just a fad?

8. Soo sung Kong et al8, have the synthesized and carried out biological evaluation of a library of resveratrol analogues as inhibitors of COX-1, COX-2 and NF-KB.

9. Marek murias et al9, have shown the Resveratrol analogues as selective cyclooxygenase-2 inhibitors: synthesis and structure- activity relationship.

10. Taksina chuanasa et al10, have reported the Anti-herpes simplex virus (HSV-1) activity of oxyresveratrol derived from Thai medicinal plant: mechanism of action and therapeutic efficacy on cutaneous HSV-1 infection in mice.

6.3 – Objective of the Study:-

The present study focuses on the:-

* Synthesis of various resveratrol/colchicines type of compounds. * Characterizations of synthesized compounds by spectral analysis (IR, 1HNMR, Mass Spectra). * Invitro cytotoxic evaluation of the synthesized compounds. 7.0

Materials and Methods:

7.1- Source of Data:

A. Journals such as , * Journal of Bio Organic and medicinal chemistry. * Journal of Toxicology and Applied pharmacology. * Journal of life sciences. * Journal of biochemical and pharmacology.

B. Internet Browsing

7.2 - Method of collection of data:

Chemicals & other reagents will be collected from standard companies. The reactions will be monitored by thin layer chromatography. The products will be purified as per standard protocols. Structure of the synthesized molecules will be confirmed by spectral analysis.

7.3 - Does the study require any investigations or interventions to be

conducted on patients or other humans or animals? If so, Please describe briefly. NO

7.4 – Has ethical clearance been obtained from your Institution in case of 7.3?

List of References:

1.Eun-Jin Lee, Hye-Young Min, Hyen Joo Park, Hwa-Jin Chunga, Sanghee Kimb,Yong Nam Hanb, Sang Kook Lee, G2/M cell cycle arrest and induction of apoptosis by a stilbenoid,3,4,5-trimethoxy-4V-bromo-cis-stilbene, in human lung cancer cells. Life Sciences, 2004; 75:2829–2839.

2. Brian W. Moran , Frankie P. Anderson , Aoife Devery , Stephen Cloonan , William E. Butler ,Sunil Varughese , Sylvia M. Draper , Peter T. M. Kenny ,Synthesis, structural characterisation and biological evaluation of fluorinated analogues of resveratrol. Bioorganic & Medicinal Chemistry, 2009; 17: 4510–4522.

3. Marek Murias, Walter Ja¨ger, Norbert Handler, Thomas Erker, Zsuzsanna Horvath, Thomas Szekeres, Hans Nohl, Lars Gille, Antioxidant, prooxidant and cytotoxic activity of hydroxylated resveratrol analogues: structure–activity relationship. Biochemical Pharmacology, 2005; 69:903–912.

4. P. Nigro , E. Bloise , M.C. Turco, A. Skhirtladze, P. Montoro,C. Pizza, S.Piacente, M.A. .. Antiproliferative and pro-apoptotic activity of novel Phenolic derivatives of resveratrol. Belisario. Life Sciences, 2007; 81: 873–883.

5. Mohammad Athar, Jung Ho Back, Xiuwei Tang, Kwang Ho Kim, Levy Kopelovich, David R. Bickers, Arianna L. Kim, Resveratrol: A review of preclinical studies for human cancer prevention. Toxicology and Applied Pharmacology, 2007; 224: 274–283.

6. SteÂphane Bastianetto, Wen-Hua Zheng & ReÂmi Quirion, Neuroprotective abilities of resveratrol and other red wine constituents against nitric oxide-related toxicity in cultured hippocampal neurons. British Journal of Pharmacology,2000; 131: 711 ± 720 7. Philipp Saiko, Akos Szakmary, Walter Jaeger, Thomas Szekeres, Resveratrol and its analogs: Defense against cancer, coronary disease and neurodegenerative maladies or just a fad? Mutation Research, 2008; 658: 68–94.

8. Soo Sung Kang, Muriel Cuendet, Denise. Endringer, Vicki L. Croy, John M. Pezzuto and Mark. Lipton, Synthesis and biological evaluation of a library of resveratrol analogues as inhibitors of COX-1, COX-2 and NF-Jb. Bioorganic & Medicinal Chemistry , 2009; 17: 1044–1054.

9. Marek Murias, Norbert Handler, Thomas Erker, Karin Pleban, Gerhard Ecker, Philipp Saiko, Thomas Szekeresband Walter Ja¨ gera, Resveratrol analogues as selective cyclooxygenase-2 inhibitors: synthesis and structure–activity relationship. Bioorganic & Medicinal Chemistry, 2004; 12: 5571–5578.

10. Taksina Chuanasa, Jurairatana Phromjai, Vimolmas Lipipun,, Kittisak Likhitwitayawuid, Mikiko Suzuki, Pornpen Pramyothin, Masao Hattori, Kimiyasu Shiraki, Anti-herpes simplex virus (HSV-1) activity of oxyresveratrol derived from Thai medicinal plant: Mechanism of action and therapeutic efficacy on cutaneous HSV-1 infection in mice. Antiviral Research, 2008; 80: 62–70.

9. Signature of the candidate (G.RAVINDRA REDDY)

10. Remarks of the Guide:

11. Name and Designation of:

11.1 Guide: M.S. SANDHYAVALI. Associate Professor Dept of Pharmaceutical Chemistry Dayananda Sagar College of Pharmacy, Kumaraswamy layout, Bangalore – 78.

11.2 Signature:

11.3 Co-Guide: Dr.B.SREEDHAR SCIENTIST Inorganic&physical chemistry division Indian Institute of Chemical Technology, Hyderabad – 500 607. 11.4 Signature

11.5 Head of the Department: Dr. V. Murugan Professor and principal Dept of Pharmaceutical Chemistry Dayananda Sagar College of Pharmacy, Kumaraswamy layout, Bangalore – 78.

11.6 Signature

12. 12.1 Remarks of the Chairman and Principal

Dr. V. Murugan Professor and principal Dept of Pharmaceutical Chemistry Dayananda Sagar College of Pharmacy, Kumaraswamy layout, Bangalore – 78

12.2 Signature